1. Field of the Invention
The present invention relates to a method for preparing oltipraz represented by Formula 1 below:

2. Description of the Related Art
Oltipraz represented by Formula 1 above was originally developed as an anti-schistosomal drug that eliminates parasites known blood flukes by Rhone-Poulenc, in 1980. However, during clinical trials, it was found that oltipraz does not have excellent drug effect relative to praziquantel that had been currently used for the treatment of parasite infections, and thus oltipraz was later abandoned.
Thereafter, in studies on a new reaction mechanism of oltipraz conducted in the 1990s, it was reported that oltipraz is effective for the inhibition of HIV propagation [Prochaska et al., 1995], the prevention and treatment of cancers, and the inhibition of HBV transcription [Chi et al., 1998].
Methods for preparing oltipraz are disclosed in U.S. Pat. No. 4,110,450, assigned to Rhone-Poulenc, issued in 1978. This patent provides two methods for preparing oltipraz, one of which is as following Scheme 2.

According to Scheme 2, however, the duration for preparation of oltipraz is too long, as 18 to 24 hours. Also, after a Claisen condensation reaction between ethyl pyrazine-2-carboxylate and ethyl propionate, separation and purification using a column are done. Furthermore, a total yield achieved after two steps of Scheme 2 above is 4.2%, which is too low for mass production.
Another method for preparing oltipraz disclosed in the above patent is as following Scheme 3.

The method of Scheme 3 includes an additional reaction step, as compared to the method of Scheme 2. Like in Scheme 2, a total yield is too low for mass production.
WO01/09118, issued on August 2001, discloses a method for preparing oltipraz as following Scheme 4:

In the above method, since sodium hydride is used as a base in a Claisen condensation reaction, there is an explosion risk of hydrogen produced during the condensation reaction. Also, since sodium hydride dispersed in oil is used, a pretreatment for oil removal is required. In particular, excess phosphorus pentasulfide (P2S5) inevitably used in the formation of a dithiolethione ring may cause severe environmental contamination. In addition, like in the above-described methods, a lengthy reaction duration is required.
Steps influencing the total yield of oltipraz in oltipraz preparation methods are a Claisen condensation reaction step in the presence of strong base and a dithiolethione ring formation step using P2S5.
In formation of dithiolethione rings from 3-oxoester compounds, a method of enhancing the yield of dithiolethione using various reagents such as P2S5, Lawesson's reagent, sulfur (S)/P2S5, or hexamethyldisiloxane/P2S5 has been reported [Tetrahedron Letters 2000, p. 9965, 17-18]. However, the yield of 3-oxoester compounds with a nitrogen-containing hetero ring is very low, and in particular, the yield of oltipraz with a pyrazinyl group is extremely low, as less than 10%.